Hypercholesterolemia, elevated blood cholesterol, is an established risk factor in the development of atherosclerosis. Therapeutic agents which control the level of serum cholesterol have proven to be effective in the treatment of coronary artery disease. While agents exist that can modulate circulating levels of cholesterol carrying lipoproteins, these agents have little or no effect on the intestinal absorption of cholesterol. Dietary cholesterol can increase the level of serum cholesterol to levels which place an individual at increased risk for the development or exacerbation of atherosclerosis. Since much of the free or unesterified cholesterol that is absorbed by intestinal mucosal cells must first be esterified by ACAT prior to its incorporation and secretion into the bloodstream in large lipoprotein particles called chylomicrons, inhibition of ACAT can reduce the absorption of dietary cholesterol. More important, the accumulation and storage of cholesteryl esters in the arterial wall is associated with increased activity of ACAT. Inhibition of the enzyme is expected to inhibit the formation or progression of atherosclerotic lesions in mammals by promoting reverse cholesterol transport.
There are a limited number of patents in the literature disclosing compounds that are useful as ACAT inhibitors in particular and antiatherosclerotic agents in general. For example, U.S. Pat. No. 4,623,662, issued to De Vries on Nov. 18, 1986, discloses ureas and thioureas as ACAT inhibitors useful for reducing the cholesterol ester content of an arterial wall, inhibiting atherosclerotic lesion development, and/or treatment of mammalian hyperlipidemia. U.S. Pat. No. 4,722,927, issued to Holmes on Feb. 22, 1988, discloses disubstituted pyrimidineamides of oleic and linoleic acids as ACAT inhibitors useful for inhibiting intestinal absorption of cholesterol.
U.S. Pat. No. 4,460,598, issued to Lautenschlager et al. on Jul. 17, 1984, discloses 2-substituted-1,4,5-triaryl imidazoles. The synthesis and the use of these compounds in the treatment of thromboembolic, inflammatory and/or atherosclerotic diseases is disclosed.
U.S. Pat. No. 4,654,358, issued to Lautenschlager et al. on Mar. 31, 1987, discloses 2-substituted-1,4,5-triaryl imidazoles. The synthesis and the use of these compounds in the treatment of inflammatory diseases, diseases of lipid metabolism, and/or hyperlipedemic diseases is disclosed.
German Laid Open Applications No. DE 3,504,679, and German Laid Open Application No. DE 3,504,680, Lautenschlager et al., published Aug. 14, 1986, discloses 1,2,4,5-tetrasubstituted imidazoles. The synthesis and the use of these compounds in the treatment of thromboembolic, inflammatory, atherosclerotic, and lipid metabolism diseases in general is disclosed.
K. Burger, et al., Synthesis, 1, 44 (1988) describe an alternative synthesis of the 5-imino-2-phenyl-4,4-bis(trifluoromethyl)-4H-imidazole system. This synthesis gives rise to compounds having a 1-mesityl substituent, which is not readily removed and therefore cannot be used to synthesize compounds of this invention, which have hydrogen or methyl at the 1-position. No biological activity was disclosed.
Co-assigned applications, U.S. Ser. No. 07/279,981 and 07/416,606 filed Dec. 5, 1988 and Oct. 10, 1989, respectively, now abandoned, relate to diarylimidazoles as inhibitors of the enzyme ACAT and their use to lower serum cholesterol in mammals.
There are no known literature references disclosing the bis-trifluoromethyl-substituted imidazolines of this invention, their use as ACAT inhibitors, or their use in the treatment of atherosclerosis.
The compounds of this invention are very potent ACAT inhibitors and/or inhibitors of cholesterol biosynthesis. As shown by the data presented below in Tables 6 and 7, the compounds of this invention inhibit the ACAT enzyme with a potency equal to or better than the potency of many of the ACAT inhibitors described in the current literature. The compounds of this invention also cause a reduction in the serum cholesterol level of normolipemic (non-cholesterol fed) hamsters, whereas in general known ACAT inhibitors fail to lower serum cholesterol levels in non-cholesterol fed animals. Compounds of the invention have also been shown to inhibit cholesterol synthesis in the liver. The compounds of this invention are systemically active and are therefore expected to be useful for the treatment of atherosclerosis. The compounds of this invention have been shown to lower serum cholesterol and to have systemic ACAT inhibitory activity following oral administration, and this invention should not be construed as limited to any particular antiatherosclerotic mechanism of action.